FprEN ISO 11979-5

SLOVENSKI STANDARD
oSIST prEN ISO 11979-5:2019
01-september-2019

Očesni vsadki (implantati) - Intraokularne leče - 5. del: Biokompatibilnost (ISO/DIS

Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO/DIS 11979-

Ophthalmische Implantate - Intraokularlinsen - Teil 5: Biokompatibilität (ISO/DIS 11979-

Implants ophtalmiques - Lentilles intraoculaires - Partie 5: Biocompatibilité (ISO/DIS

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting

on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address

Foreword ........................................................................................................................................................................................................................................iv

Introduction ................................................................................................................................................................................................................................vi

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 2

4 General requirements applying to biocompatibility evaluation of intraocular lenses ..............2

5 Physicochemical tests...................................................................................................................................................................................... 3

5.1 General ........................................................................................................................................................................................................... 3

5.2 Physical/Chemical description ................................................................................................................................................. 3

5.3 Exhaustive extraction test ............................................................................................................................................................. 4

5.4 Test for leachables ................................................................................................................................................................................ 4

5.5 Test for hydrolytic stability .......................................................................................................................................................... 5

5.6 Photostability test ................................................................................................................................................................................ 5

5.7 Nd-YAG laser exposure test ........................................................................................................................................................... 6

5.8 Evaluation of insoluble inorganics ......................................................................................................................................... 7

6 Biological tests ........................................................................................................................................................................................................ 7

6.1 General ........................................................................................................................................................................................................... 7

6.2 Tests for genotoxicity ........................................................................................................................................................................ 7

6.3 Tests for sensitization ....................................................................................................................................................................... 8

6.4 Ocular implantation test ................................................................................................................................................................. 8

Annex A (normative) Exhaustive extraction test ..................................................................................................................................... 9

Annex B (normative) Test for leachables ......................................................................................................................................................13

Annex C (normative) Hydrolytic stability .....................................................................................................................................................15

Annex D (normative) Photostability test ......................................................................................................................................................18

Annex E (normative) Nd-YAG laser exposure test ................................................................................................................................20

Annex F (normative) Supplemental conditions of test for local effects after implantation ....................22

Annex G (normative) Ocular implantation test ......................................................................................................................................23

Bibliography .............................................................................................................................................................................................................................27

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the

different types of ISO documents should be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

Any trade name used in this document is information given for the convenience of users and does not

For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO's adherence to the

World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following

This document was prepared by Technical Committee ISO/TC 172, Optics and photonics, Subcommittee

This third edition cancels and replaces the second edition (ISO 11979-5:2006), which has been

— Clarification of test material and parent IOLs, added the requirement for a biological evaluation plan

— Combination and re-write of physicochemical test methods and objectives (Section 5.1)

— Added requirement for physical/chemical description and contaminants (Section 5.2)

— Adjustment of ratio for material and extraction medium in genotoxicity testing (Section 6.2)

— In hydrolytic stability, products are their own control for spectral transmittance and dioptric power

— Removed the allowance of representative test material for photostability testing, added the

— Duration of subcutaneously or intramuscularly implantation increased from 4 weeks to 3 months

— Duration of ocular implantation test in rabbits reduced from 6 to 3 months (Annex G).

This part of ISO 11979 follows the general principles given in ISO 10993-1. ISO 10993-1 describes the

principles governing the biological evaluation of medical devices, the definitions of categories based

on the nature and duration of contact with the body, and selection of appropriate tests. Other parts of

ISO 10993 present biological test methods, tests for ethylene oxide residues, tests for degradation and

This part of ISO 11979 specifies particular requirements for the biocompatibility evaluation of materials

for intraocular lenses (IOLs) including the processing conditions to produce them. These requirements

include evaluation of physicochemical properties that are relevant to biocompatibility. It also gives

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements of this document. For dated references, only the edition cited applies. For

undated references, the latest edition of the referenced document (including any amendments) applies.

ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk

ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements

ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and

ISO 10993-5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity

ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation

ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization

ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference

ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for

ISO 11979-2, Ophthalmic implants — Intraocular lenses — Part 2: Optical properties and test methods

ISO 11979-3, Ophthalmic implants — Intraocular lenses — Part 3: Mechanical properties and test methods

ISO 18369-4:2006, Ophthalmic optics — Contact lenses — Part 4: Physicochemical properties of contact

ISO/TS 21726, Biological evaluation of medical devices — Application of the threshold of toxicological

ISO/TR 22979, Ophthalmic implants — Intraocular lenses — Guidance on assessment of the need for clinical

For the purposes of this document, the terms and definitions given in ISO 11979-1 apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

The evaluation of the biocompatibility of the test material (refer to 11979-1 and Table 1 for definition

of test material and allowance of representative samples) shall start with an initial assessment of risk

in accordance with ISO 14971. The tests described in Clause 5 shall first be performed to characterize

the physicochemical properties of the intraocular lens. The evaluation of the material for biological

safety shall then be undertaken in accordance with the principles and requirements of ISO 10993-1

and ISO 10993-2, taking into consideration the results from the physicochemical tests. Following the

risk assessment, establish a biological evaluation plan in accordance with ISO 10993-1 addressing the

Furthermore, the risk assessment shall include an assessment of the potential for material changes

such as calcification. This risk assessment should consider the history of clinical use of the material,

Carry out the biocompatibility testing in accordance with ISO 10993-1, ISO 10993-3, ISO 10993-5,

ISO 10993-6, ISO 10993-10, ISO 10993-17 and ISO/TS 21726 and as noted in this part of ISO 11979.

The pre-existing information on the material and all the information obtained in the evaluation process

shall be integrated in an overall risk benefit assessment in accordance with ISO 14971.

Sample, manufactured and processed using a procedure equivalent to that used for the

intraocular lens, that has the same central thickness as the final product (typically 20.0 D IOL).

Sample, manufactured and processed using a procedure equivalent to that used for the

intraocular lens, that has the same central thickness as the final product (typically 20.0 D IOL).

To allow for dimensional differences between human and animal eyes, the IOL could require

The physicochemical tests listed in Table 2 shall be performed to characterize the physicochemical

properties of the IOL and to facilitate an analysis of any risk introduced by chemical compounds which

may result from processing, treatment in use, or (simulated) ageing of the test material. A risk-based

approach should be used; the results of the tests in Table 2 should be used as input for a risk assessment

and further testing when deemed necessary, in accordance with ISO 14971. The risk assessment should

To facilitate the explaining of physical and chemical test results, the manufacturer shall provide a

description of each of the components in the formulation. For description of each component the

a) Name — Provide the chemical name and Chemical Abstracts Service (CAS) registry number;

c) If the component material is derived from biological sources, the organism from which it is obtained

a) Exhaustive extraction To identify and quantify the total amount of extractable material that is

c) Hydrolytic stability To identify and quantify possible degradation products due to hydrol-

d) Photostability against To characterize the effect of UV/Vis irradiation on the optical, mechan-

ultraviolet/visible (UV/Vis) ical and chemical properties of the IOL and to assess the risk for poten-

e) Stability against Nd-YAG laser To identify the effect of Nd-YAG laser treatment on the chemical prop-

exposure erties of the IOL and to assess the risk for potentially harmful effects of

f) Insoluble inorganics To quantify the levels of insoluble inorganics which may result from

The test material shall be tested for extractables under exhaustive extraction conditions in accordance

with the method described in Annex A. Alternate methods can be used, provided that they have been

b) The test material shall be weighed before and after extraction and any change in mass shall be

c) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction

for possible extractable components of the material, such as process contaminants, residual

The results shall be evaluated to assess the risk for potentially harmful effects due to extractable

All extractables shall be evaluated toxicologically according to ISO 10993-17 and ISO/TS 21726.

The test material shall be tested for leachables under simulated physiological conditions in accordance

with the method described in Annex B. Alternative analytical methods can be used that are reflective of

b) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction

for possible extractable components of the material, such as process contaminants, residual

The results shall be evaluated to assess the risk for potentially harmful effects due to leachable

All leachables shall be evaluated toxicologically according to ISO 10993-17 and ISO/TS 21726.

Hydrolytic stability testing shall be conducted in accordance with the method described in Annex C.

a) The study shall be designed to evaluate the stability of the material in an aqueous environment at

35 °C ± 2 °C for a period of at least five years or at an elevated temperature for a simulated exposure

NOTE Five years is considered sufficiently long to show changes when the product is not hydrolytically

stable and is considered appropriate since only limited test acceleration is possible.

b) The simulated exposure time is to be determined by multiplying the actual study time with the

c) The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities

d) The test material shall be examined by light microscopy at 10´ or higher and by scanning electron

microscopy (SEM) at 500´ or higher before and after testing. The test material shall be compared

with the untreated material and there shall be no significant difference in surface appearance (e.g.

e) Optical transmittance spectra of the test material in the ultraviolet and visible spectral regions

(UV/Vis) shall be recorded before and after testing. By comparison of the spectra, assurance shall

f) The dioptric power shall be determined before and after testing if finished IOLs are used in the

testing. The refractive index shall be determined instead if a facsimile material is used. There

shall be no average absolute change in diopter power greater than 0,25 D for a 20 D lens or a

corresponding change in refractive index comparing before testing and after exposure to the

The results shall be evaluated to assess the risk for potentially harmful effects due to instability of the

All degradation products shall be evaluated toxicologically according to ISO 10993-17 and ISO/

a) There shall be no changes in appearance of the irradiated test material when compared with non-

irradiated test material, such as bulk and surface defects induced by photo irradiation.

b) No significant change shall be detected between the UV/Vis spectra, power and resolution of the

c) The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities

d) Furthermore, when performing the testing for anterior chamber IOLs, it shall be shown that no

significant change in mechanical properties of the irradiated test material has occurred when

The results shall be evaluated to assess the risk for potentially harmful effects due to instability of the

All chemical substances detected after irradiation shall be evaluated toxicologically according to

NOTE 1 The loops of implanted anterior chamber IOLs are exposed to radiation, hence the rationale for

NOTE 2 The following parameters have been found to be relevant to in situ exposure of an IOL to UV radiation:

a) in vivo UV-A radiation intensity in the range 300 nm to 400 nm at the position of the IOL at diffuse light

The internationally accepted estimation for full intensity of sunlight is an average of 1 kW/m = 100 mW/cm in

sunny areas close to the Tropic of Cancer. The portion of near ultraviolet wavelengths in the 300 nm to 400 nm

range is approximately 6,5 % of the total intensity, i.e. about 6,5 mW/cm . Intraocular lenses are exposed to

sunlight which reaches behind the cornea and the aqueous humour. Within the spectrum of sunlight, that part

of the near ultraviolet radiation which is not absorbed by the cornea and the aqueous humour and which can

potentially damage IOLs by photochemical degradation, amounts to approximately 40 % to 50 % of the total

UV-A radiation. Assuming that the cornea and the aqueous humour absorb 50 % of the UV-A, the IOL is exposed to

an irradiation of 3,25 mW/cm in the 300 nm to 400 nm range at full intensity of sunlight. The diffuse, reflected

light intensity is estimated to be one-tenth of the above value. The irradiation of an intraocular lens in vivo is

d) intensity factor (n): 1 (i.e. maximum intensity under consideration of sunny regions).

The in vitro test period (T , in days) can be calculated using the following equation (see Reference [1]), with (I )

being the in vitro intensity of the radiation source in the 300 nm to 400 nm range:

The effect of Nd-YAG laser exposure shall be evaluated in accordance with Annex E.

The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities after

NOTE Nd-YAG laser treatment can lead to a higher concentration of released chemicals during the laser

The results shall be evaluated to assess the risk for potentially harmful effects, due to instability of the